TAMable tumor-associated macrophages in response to innate RNA sensing.

2012·0.21 MB·English

by  Seya, Tsukasa

AuthOr’S VIew
OncoImmunology 1:6, 1000-1001; September 2012; © 2012 Landes Bioscience
TAMable tumor-associated macrophages
in response to innate RNA sensing
tsukasa Seya,* hiroaki Shime and Misako Matsumoto
Department of Microbiology and Immunology; Graduate School of Medicine; hokkaido university; Sapporo, Japan
Keywords: TLR3, TICAM-1, tumor-infiltrating macrophages, polyI:C, immunotherapy
Antitumor effect of PolyI:C (a viral dsrNA analog) has been attributed to dendritic cell (DC)-maturation activity, that drives
antitumor NK cells, DC cross-presentation, cytotoxic t lymphocytes and many IFN-inducible genes. According to a recent
paper, tumor-infiltrating M2 macrophages are found to become an additional antitumor effector through polyI:C response.
Interferon (IFN), now categorized as phagocytes,2 such as dendritic cells (DC) case also. Shime et al. applied KO mice
Type I, was discovered by Isaacs and and macrophages. dsRNA is delivered models for analyzing the signaling path-
Lindeman in 1957. Soon after their dis- through a unique pathway involving way by which the polyI:C-derived tumor
covery, it was expected to be a fascinating Raftlin,3 then the endosomal TLR3 passes regression occurs. Ultimately, their con-
medicine opposing to virus infection and the signal to the adaptor TICAM-1.2 The clusion was that tumor-infiltrating mac-
cancer development. Type I IFN induc- multiple functionality of polyI:C may rophages (Mf) characterized by CD11b+/
ing activity was assigned to the signature reflect its divergent receptor usage, and F4/80+/Gr-1low markers with sustaining
of double-stranded RNA generated from knockout mouse (KO) studies have there- tumor-supporting phenotype, M2, serves
viruses, and its synthetic analog, polyI:C, fore been indispensable for determination as a target for polyI:C and changes their
was confirmed to serve as an effective of the role of each receptor in antitumor properties to antitumor, M1-like, behav-
inducer of Type I IFN. Talmadge et al. immunity. ing like a tumoricidal effector. In these
showed that polyI:C mixed with polyL In mouse models, growth retardation Mf, TLR3/TICAM-1 pathway, but not
Lysine and methylcellulose (polyI:CLC) of syngenic implanted tumor has been the IPS-1 pathway, is also mandatory for
effected dramatic regression of syngenic reportedly observed by administration TNFα production and tumor regression.
implant tumors in mice. They suggested of polyI:C, which is now attributable to Indeed, the marker profile of the Mf was
this reagent might be applied to antitumor liberated Type I IFN and maturation of similar to those reported as M2 Mf or
therapy. In line with these reports, there DC, that drives NK and killer T cells.4,5 tumor-associated Mf (TAM). It is notable
have been many reports indicating that The mechanisms whereby these effec- that they have high expression levels of
spontaneous tumor regression sometimes tor cells are introduced by dsRNA are TLR3. Hence, the polyI:C tumor growth
occurrs in cancer patients when they are being elucidated on a molecular level: the retardation is mechanically multifarious
exposed to viruses or viral vectors. TLR3/TICAM-1 pathway for dsRNA and involves TNFα hemorrhagic necrosis.
PolyI:C induces Type I IFN and recognition in DC is involved in effec- TLR3 is highly expressed in CD8+
inflammatory cytokines. In addition, it tor driving. In a recent paper, Shime et splenic DC and CD103+ non-lymphoid
may contribute to raising cellular immu- al. additionally identified the third anti- DC in mice,8 and they are strong induc-
nity. According to recent progress in tumor effector induced by ip polyI:C ers for cross-priming of CD8 T cells,5,8
pattern recognition of innate immunity, administration.6 PolyI:C acted on tumor- namely cytotoxic T lymphocytes (CTL).
polyI:C is a ligand for multiple recep- infiltrating macrophages and induced TLR3-positive bone marrow-derived
tors, including PKR, RIG-I, MDA5 and tumor growth retardation in some tumor DC also reportedly induce Type I IFN
TLR3.2 Virus replication usually ampli- species. Administration of polyI:C rapidly and potent antitumor NK cell activity.4
fies dsRNA production inside the cyto- (< 12 h) led to tumor hemorrhagic necrosis Thus, polyI:C functions through TLR3+
plasm of affected cells and stimulates the followed by tumor regression. The results myeloid cells to facilitates antitumor cellu-
cytoplasmic RNA sensors. In contrast, appear to resemble an earlier report by lar immunity encompassing at least three
TLR3 is activated when dsRNA gener- Old’s group on the TNFα-mediated fibro- distinct routes, NK cell activation, CTL
ated in infected cells is released and inter- sarcoma regression.7 In fact, TNFα par- proliferation and conversion of TAM to
nalized into the endosome of bystander ticipated in hemorrhagic necrosis in this an tumoricidal effector (Fig. 1). Hence,
*Correspondence to: Tsukasa Seya; Email: [email protected]
Submitted: 02/27/12; Revised: 03/02/12; Accepted: 03/02/12
http://dx.doi.org/10.4161/onci.19894
1000 OncoImmunology Volume 1 Issue 6
AuthOr’S VIew AuthOr’S VIew
Figure 1. PolyI:C induces three antitumor effectors via different routes. Antitumor activity of polyI:C against tumor cells are assessed in mouse tumor-
implant models. A unique point in this review is the third pathway where tumor-infiltrating myeloid cells are involved, effectively damages Lewis Lung
carcinoma cells. this tumoricidal activity is mediated by the tICAM-1 pathway in the myeloid cells, and attributed to tNFα. Although polyI:C is i.p.
administered, it acts on tumor-infiltrating Mf and converts them to antitumor effectors.
5. Azuma M, Ebihara T, Oshiumi H, Matsumoto M, Seya
the Janeway/Medzhitov concept9 may be issue and further clarified the importance T. Cross-priming for antitumor CTL induced by solu-
adaptable to tumor immunology that pat- of the TICAM-1 pathway in triggering ble Ag + polyI:C depends on the TICAM-1 pathway in
mouse CD11c+/CD8α+ dendritic cells. OncoImmunol
tern recognition receptor (PRR) stimula- induction of antitumor Mf in addtion
2012; In press.
tion by a specific ligand triggers innate to NK cells and CTL.6 These sequential 6. Shime H, Matsumoto M, Oshiumi H, Tanaka S,
immune response and facilitates establish- studies, together with the direct apoptotic Nakane A, Iwakura Y, et al. Toll-like receptor 3
signaling converts tumor-supporting myeloid cells
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